Bioassays are widely used to observe changes in the status of cells and the response of cells to a drug, etc. In general, cultured cells have been frequently used in conventional bioassays. Because assays in such a system are carried out using a plurality of cells, an average value from a population of cells has been viewed as if it were the property of a single cell.
Actually it is rare, however, for the cell cycle to be synchronized within a population, and cells express their proteins at different points in the cell cycle. Therefore, every analysis of response to a stimulus is always accompanied by the problem of fluctuation.
In other words, because the universal responses of cellular reaction mechanisms themselves fluctuate, only averages of the responses can be obtained. Methods of synchronized culturing, etc., have been developed to solve these problems. However, using groups of cells that are always at the same stage means that such cells must be supplied continuously, and that has been a hindrance to the widespread acceptance and use of bioassays.
Moreover, there are two types of stimuli (signals) to cells, i.e., ones provided by the amounts of signal substances, nutrients, and dissolved gases in the solution surrounding the cells, and ones caused by physical contact and intercellular interactions with other cells. As a result, these fluctuations have been difficult to evaluate.
The problems of physical contact and intercellular interactions can be solved to a certain extent by carrying out the bioassay with a cluster of cells such as a tissue fragment. Unlike cultured cells, however, cell clusters with uniform features cannot always be obtained in such a case. Thus, there is a problem because the resulting data is scattered, and information gets buried within the population.
As disclosed in Japanese Patent Application Laid-open No. 2006-94703 (Patent Document 1), the inventors of the present application have proposed a cell aggregate microarray (bioassay chip) with a structure constituting a plurality of cell culturing compartments for enclosing the cells in a specific spatial configuration, having adjacent compartments mutually linked by grooves or tunnels too narrow for a cell to pass therethrough, and as needed, having in the grooves, tunnels, or cell culturing compartments a pattern of a plurality of electrodes for measuring changes in cell action potential in order to carry out measurements by a data processing model using each individual cell in a group of cells as the minimum structural unit thereof.
Patent document 1: Japanese Patent Application Laid-open No. 2006-94703
In conventional bioassays, either cells have been treated as a tissue fragment, or cultured cells have been treated as a single cell. As noted in the aforementioned discussion of background art, there is a problem when the number of cells becomes too large because the resulting data becomes an average value, and the response to a drug, etc., cannot be accurately ascertained therefrom. Whenever cells are used one by one, however, cells that originally function as cells of a multicellular tissue are used as cells in an isolated, independent state. As a result, the effects of intercellular interactions no longer appear, and as can be expected, there is a problem in accurately obtaining a response to a drug, i.e., the bioassay data.
When evaluating the effect of a drug on a cell, it is important to develop a device and system wherein cell potential and cell morphology can be measured accurately on a single cell basis, and wherein a cytotoxicity test can be measured accurately in the form of cell potential and cell morphology on a single cell basis.
Additionally, as for cardiomyocytes and fibroblasts, it is important to develop a device and system wherein the propagation of a pulse wave from an adjacent cardiomyocyte or fibroblast can be measured accurately on a single cell basis in terms of cell morphology and cell potential, and wherein a test for toxicity of a drug on a cardiomyocyte can be accurately performed by measurements of cell potential and cell morphology on a single cell basis.